A large Danish study supports a robust and long-term bidirectional relationship between epilepsy and depression, with implications for diagnosis and patient care.

Eva Bølling-Ladegaard

The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” Eva Bølling-Ladegaard, MD, PhD student, Department of Clinical Medicine (Neurology), Aarhus University, Denmark, told Medscape Medical News.

“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Bølling-Ladegaard said.

The study was published online November 22 in Neurology.

Epilepsy Then Depression

The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.

In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).

The rate of developing depression was increased nearly twofold among people with epilepsy compared to the matched population who did not have epilepsy (adjusted hazard ratio [aHR], 1.88; 95% CI: 1.82 – 1.95).

The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.

The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared to 0.59% and 3.92% in the reference population.

The highest rate of depression after epilepsy was among individuals aged 40 to 59 years, and the lowest was among those aged 0 to 19 years at first epilepsy diagnosis.

Depression Then Epilepsy

The rate of developing epilepsy was increased more than twofold among patients with incident depression compared to the matched population who were without depression (aHR, 2.35; 95% CI: 2.25 – 2.44).

As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.

The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared to 0.32% and 2.06% in the reference population.

The rate of epilepsy was highest among those aged 0 to 19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.

For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI: 1.59 – 1.67) and 1.48-fold (95% CI: 1.44 – 1.53), respectively, compared to matched individuals without asthma.

Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.

“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” Bølling-Ladegaard told Medscape Medical News.

“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.

Clinical Implications

Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, Texas, noted that the link between epilepsy and depression is “well-known.”

“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Haneef told Medscape Medical News.

“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.

The findings do have implications for care, he said.

“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Haneef said.

“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.

“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Haneef said.

The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Bølling-Ladegaard and Haneef have disclosed no relevant financial relationships.

Neurology. Published online November 22, 2022. Abstract

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